Linking To And Excerpting From “Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer’s disease in humans”

Posted on November 15, 2025 by Tom Wade MD

Today, I review, link to, and excerpt from Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer’s disease in humans [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Commun Med (Lond)
. 2025 Jan 9;5(1):11. doi: 10.1038/s43856-024-00682-w.

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Abstract

Background

Alzheimer’s disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.

Method

In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform.

Results

Here we identified substantial changes in response to MMKD intervention, aside from metabolic changes associated with a ketogenic diet, we identified a a global elevation across all plasmanyl and plasmenyl ether lipid species, with many changes linked to clinical and biochemical markers of AD. We further validated our findings by leveraging our prior clinical studies into lipid related changeswith AD (n = 1912), and found that the lipidomic signature with MMKD was inversely associated with the lipidomic signature of prevalent and incident AD.

Conclusions

Intervention with a MMKD was able to alter the plasma lipidome in ways that contrast with AD-associated patterns. Given its low risk and cost, MMKD could be a promising approach for prevention or early symptomatic treatment of AD.

Subject terms: Cognitive neuroscience, Alzheimer’s disease, Metabolomics, Phospholipids

Plain language summary

Previous research has suggested that different diets might alter the risk of a person developing Alzheimer’s disease. We compared the blood of 20 older adults, some with memory impairment, following a change in diet. The two diets we compared were the Modified Mediterranean Ketogenic and American Heart Association Diets. The changes that were seen following consumption of the Mediterranean-ketogenic diet were the opposite to those typically seen in people with Alzheimer’s disease or those likely to develop it. These data suggest adopting this diet could potentially be a promising approach to slow down or prevent the development of Alzheimer’s disease. Aligning these results with previous larger clinical studies looking at lipids, we identified that these changes were opposite to what was typically seen in people with Alzheimer’s disease or those likely to develop it. As this diet was generally safe and inexpensive, this intervention could be a promising approach to mitigate some risk Alzheimer’s disease and help with early symptoms.

Neth, Huynh et al. evaluate whether consuming a modified Mediterranean ketogenic diet alters parts of the plasma lipidome associated with development of Alzheimer’s disease (AD). Consuming the ketogenic diet alters the plasma lipidome, with changes inversely linked to Alzheimer’s disease (AD) biomarkers and lipidomic signatures.

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and has an increasing incidence. Despite extensive research, efforts to identify clinically meaningful disease-modifying therapies have been difficult–, making AD one of our most significant health challenges. The pathophysiologic hallmarks of AD occur long before the onset of clinical symptoms. As such, there is great interest in understanding the brain and systemic changes that occur in patients at risk for AD in hopes of preventing the development of progressive neurologic decline.

The traditional ketogenic diet (KD) was developed at the Mayo Clinic in 1921 for the treatment of epilepsy,, and continues be a part of clinical care for patients who have medically intractable epilepsy. KD is a high-fat and low-carbohydrate diet. This transition of the body’s primary metabolic fuel from glucose to fats and ketones leads to ketosis, or the production of ketone bodies. The KD has proven to be highly effective in the control of seizures, which has led to its continued clinical use,. A modified KD with the ability to sequentially increase carbohydrates has shown similar efficacy in seizure control, which improves long-term adherence.

There are clear metabolomic changes in AD, highlighted by altered phospholipid and sphingolipid metabolism which begin in preclinical and symptomatic AD. Changes have also been noted in bile acids, triglycerides and lipoproteins, in cholesterol metabolism and clearance through bile acids, and in ether lipids, including plasmalogens, branched-chain amino acids and acylcarnitines–. Our Alzheimer’s Disease Metabolomics Consortium under the Accelerating Medicine Partnership for Alzheimer’s Disease has generated large data sets of metabolomics and lipidomics from large AD and community studies that defined many of these changes, and in which peripheral changes were connected with imaging changes and amyloid, tau and neurodegeneration markers of disease–.

Lipids are fundamental components of cellular structure and function, particularly in the brain, which is one of the most lipid-rich organs. Lipids are a major constituent of membranes and synapses, which are impaired and ultimately lost throughout the course of AD,. Thus, studying lipids in the context of preclinical and early symptomatic AD (mild cognitive impairment or MCI) provides an important window into crucial lipid changes and how they may be modified by intervention prior to advanced neuropathologic changes.

Lipidomics is a powerful tool used to study the diversity of multiple lipid classes and species. We have previously used a targeted lipidomics platform to map the key plasma lipid signatures in MCI and AD dementia across two large clinical cohorts, and found concordant changes in ether lipids, sphingolipids, triglycerides, and phosphatidylethanolamine. The lipid aberrations in AD serve as an important therapeutic target, particularly as many of the affected lipid classes have structural and functional roles in the plasma membrane involving signaling and synaptic function,,–. The importance of lipids in AD is highlighted by APOE, a lipoprotein gene. APOE remains the largest genetic risk factor for sporadic AD, with the Ɛ4 isoform dramatically increasing the risk of AD,. Conversely, the APOE Ɛ2 genotype reduces the risk of AD, and we have previously identified that around one-third of the protective effects of APOE Ɛ2 are potentially mediated through peripheral ether lipids.

Here we use a robust targeted lipidomics platform in which 784 species across 47 classes are measured to map the effect of a modified mediterranean ketogenic diet (MMKD) on the plasma lipidome in patients at risk for AD with and without cognitive impairment (Table 1). The primary outcomes of this study have been previously reported. Here we report substantial changes to the plasma lipidome with the modified ketogenic diet, and further identify that these changes were inversely related to a previously established signature of the AD lipidome.

Table 1.

Participant characteristics for full sample set at study baseline

All (n = 20) CN (n = 11) MCI (n = 9)
Age, years 64.3 (6.3) 64.9 (7.9) 63.4 (4.0)
Female Sex 15 (75%) 9 (81.8%) 6 (66.7%)
Black race 7 (35%) 2 (18.2%) 5 (55.6%)
APOE Ɛ4-positive 6 (31.6%) 2 (20%)^ 4 (44.4%)
Education, years 16.1 (2.5) 16.5 (2.3) 15.7 (2.9)
BMI, kg/m2 28.4 (5.7) 26.9 (6.2) 30.3 (4.7)
MMSE 28.7 (1.1) 28.9 (1.0) 28.3 (1.2)
Glucose, mg/dL 97.6 (18.3) 93.9 (11.4) 102.1 (24.4)
BHB, mmol/L 0.23 (0.27) 0.35 (0.31)+ 0.1 (0.14)+
Insulin, μIU/mL 8.3 (6.1) 5.2 (3.4)+ 12.0 (6.8)+
HbA1c, % 5.9 (0.3) 5.9 (0.2) 6.1 (0.4)
Total Chol, mg/dL 215.2 (43.7) 200.5 (42.1) 233.2 (40.6)
HDL Chol, mg/dL 67.4 (25.8) 69.5 (25.8) 64.8 (27.1)
VLDL Chol, mg/dL 20.0 (11.1) 15.2 (6.2)+ 25.8 (13.2)+
LDL Chol, mg/dL 121.5 (41.2) 104.1 (45.6)+ 142.7 (24.2)+
Triglycerides, mg/dL 99.8 (55.7) 75.5 (30.5)+ 129.4 (66.4)+
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Table values are mean (SD) or N (%). +Denotes a difference between cognitively normal (CN) and mild cognitive impairment (MCI), p < 0.05, using T-test for continuous and Fisher’s exact test for categorical variables. ^APOE genotype information unavailable for one participant. MMSE mini mental status exam score, BMI body mass index, BHB beta-hydroxybutyrate, HbA1c hemoglobin A1c.

Methods

Study participants

We included participants at risk for AD based on baseline cognitive dysfunction (MCI) diagnosed by expert physicians and neuropsychologists using National Institutes of Health – Alzheimer’s Association MCI criteria, or who had subjective memory complaints using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) criteria. All had prediabetes as defined by American Diabetes Association guidelines, with a screening hemoglobin A1c of 5.7–6.4%. Study exclusion criteria included a prior diagnosis of neurological or neurodegenerative illness (except MCI), major psychiatric disorder (well-controlled depression was allowed), prior stroke, current use of diabetes and lipid-lowering medications, or current use of medications that impact central nervous system activity (i.e., anti-seizure medications, anti-psychotics, opioids). The study was designed to better understand the relationship between insulin resistance, AD risk, and targeted interventions, thus prediabetes was an inclusion criterion for this clinical trial.

43.Albert, M. S. et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 270–279 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar][Ref list]

44.Risacher, S. L. et al. APOE effect on Alzheimer’s disease biomarkers in older adults with significant memory concern. Alzheimer’s. Dement.11, 1417–1429 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar][Ref list]

42.Neth, B. J. et al. Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer’s disease: a pilot study. Neurobiol. aging86, 54–63 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar][Ref list]

The protocol was approved by the Wake Forest Institutional Review Board (ClinicalTrials.gov Identifier: NCT02984540). Written informed consent was obtained from all participants. Study partners (next of kin, who could legally consent for study enrollment) also reviewed consent, as is standard practice in research studies of participants with cognitive impairment. Study partners agreed that enrollment was appropriate after understanding the potential risks of participation. Participants were medically supervised by clinicians, with safety monitoring overseen by the Wake Forest Institutional Data and Safety Monitoring Committee. The analysis’ included in the present study were not pre-specified in the study protocol, as lipidomics was not designed to be included in this study. However, given the importance of the lipidome in brain health and disease, we have focused on this extensive post hoc analyses.

Procedure

This was a randomized crossover pilot trial in which participants consumed either a Modified Mediterranean-Ketogenic Diet (MMKD) or the American Heart Association Diet (AHAD) for 6 weeks. This was followed by a 6-week washout period, after which the diet not previously used was consumed for 6 weeks (Supplementary Fig. 4). Participants were instructed to resume their pre-study diet during the washout period. Randomization to the initial diet was through a random number generator. See Neth et al. for complete details.

Diet Intervention and Education

The experimental diet (MMKD) was a modified ketogenic diet, which has increasingly been utilized in medically intractable epilepsy due to its increased tolerability and similar efficacy to the traditional ketogenic diet. The target macronutrient composition (expressed as % of total calories) was 5–10% carbohydrate, 60–65% fat, and 30% protein. Note that this is in line with the “Modified Atkins Diet”, although it contains less fat than a traditional KD, which contains about 90% fat by calories. Daily carbohydrate consumption was targeted at <20 g/day. Participants were encouraged to avoid store-bought products marketed as “low-carbohydrate” and artificially sweetened beverages. Extra virgin olive oil was supplemented, and participants were encouraged to eat fish, lean meats, and nutrient-rich foods as the source of carbohydrates (i.e., green leafy vegetables, nuts, berries).

Our control diet (AHAD) was adapted from the low-fat American Heart Association Diet. The target composition of the AHAD was 55–65% carbohydrates, 15–20% fat, and 20–30% protein. Daily fat intake was targeted at <40 g/day. Participants were encouraged to eat plentiful fruits, vegetables, and fiber-laden carbohydrates.

A registered dietitian developed daily meal plans for each participant based upon their food preferences and caloric needs as determined by a pre-study 3-day food diary, body composition, and activity level. Participants had weekly diet education visits (either in-person or by phone) starting one week prior to the start of each diet and continuing throughout the remainder of the intervention. Participants maintained a daily food record that was reviewed at these visits. Both diets were eucaloric and targeted to each participant’s baseline caloric needs with a goal of keeping weight neutral throughout the course of the study. Participants were asked to keep their exercise and physical activity level stable throughout the study. Adherence was assessed by capillary ketone body (beta-hydroxybutyrate) using the Nova Max Plus®  and using participant subjective reports. Participants were required to supply their own food with a food stipend of $25/week provided to defray higher food costs. Participants received a daily multivitamin supplement (Centrum® Silver®) during both diets. The following supplements were not allowed for the duration of the study: resveratrol, CoQ10 (coenzyme Q10), coconut oil/other medium-chain triglyceride-containing supplements, or curcumin.

Please see the article for details of “Blood collection and processing”, “Lipid extraction and lipidomic analysis (plasma)”, “Lumbar Puncture”, and “CSF measures”.

Neuropsychological evaluation

At baseline and after each diet, study participants completed assessments of immediate and delayed memory. Tests included the Free and Cued Selective Reminding Test (FCSRT), Story Recall (modification of the episodic memory measure from the Wechsler Memory Scale-Revised), and the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog12). Cognition was assessed before and after each diet, and at follow-up. Different versions of selected tests were utilized to mitigate the impact of practice effects on cognitive performance.

50.Grober, E., Sanders, A. E., Hall, C. & Lipton, R. B. Free and cued selective reminding identifies very mild dementia in primary care. Alzheimer Dis. Assoc. Disord.24, 284–290 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar][Ref list]

51.Wechsler D. Wechsler Memory Scale-Revised. San Antonio, Texas: Psychological Corporation; 1987. [Ref list]

52.Rosen, W. G., Mohs, R. C. & Davis, K. L. A new rating scale for Alzheimer’s disease. Am. J. Psychiatry141, 1356–1364 (1984). [DOI] [PubMed] [Google Scholar][Ref list]

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Results

The modified Mediterranean ketogenic diet significantly altered the plasma lipidome at a class level

Lipidomic measures were taken on all plasma samples collected in the study. We examined the impact of the MMKD and American Heart Association Diet (AHAD) on the plasma lipidome using linear mixed models after each dietary intervention. Significant impacts on the plasma lipidome were observed in the MMKD (Fig. 1a) with 18 of the 47 categorized lipid classes presenting an association with a false discovery rate (FDR) corrected p value < 0.05. In contrast, the AHAD had no associations after FDR correction, but 12 lipid classes presented with nominal associations with uncorrected p < 0.05 (Supplementary Data 1). There were minimal impacts to the lipidome after washout periods relative to pre-study baseline (Supplementary Fig. 1).

Discussion

As far as we are aware, this is the first clinical study to assess the impact of a ketogenic dietary intervention on the lipidome in patients at risk for AD. We used a powerful targeted lipidomics platform to map the effect of a KD on the plasma lipidome to better define the metabolic changes that underlie the potential therapeutic benefits in AD. We found four key findings: (1) MMKD but not AHAD had a large impact on the plasma lipidome, (2) some lipidomic changes were more pronounced in those with baseline cognitive impairment, and most importantly (3) MMKD-induced changes were inversely related to patterns previously found in AD; which suggests that (4) MMKD may be effective in reversing the undesirable AD lipidomic profile.

We previously showed that a modified ketogenic diet (MMKD) improved key CSF AD biomarkers, imaging measures, and cognition in a pilot study of adults at risk for AD. In the present study, we sought to examine the effects of this intervention on the plasma lipidome. The MMKD had a considerable impact on the plasma lipidome at both the class and species level, although we found strong MMKD-associated changes in lipid species that were not seen at the class level.

Ketosis is the process in which the body shifts to metabolize fats rather than carbohydrates and is observed in low-glucose situations. This process is essential for providing peripheral ketones to the brain for energy, as the brain is unable to metabolize fats in the same manner. Our data reflects this process in the periphery, where complex triglycerides are broken down, resulting in the corresponding increases to free- or carnitine-bound fatty acids. In ageing and AD, brain energy homeostasis plays an important role and is believed to be impaired, with some research indicating a central dysregulation of glucose metabolism,. Ketone bodies transported into the brain are believed to provide an alternative energy source to rectify some of the perturbation in glucose metabolism in AD.

All free fatty acid species were increased after the MMKD, but the strongest associations were driven by several PUFAs (22:5, 22:4 and 22:6). This is similarly reflected in the minimal declines of only PUFA-esterified triglycerides. Both hydroxylated species of acylcarnitines (16:0, 16:1 and 18:1 fatty acid) increased, with similar associations in the nonhydroxylated species, which highlights both increases to carnitine shuttling, and hydroxylation for oxidation. Both TG and FFA can cross the blood-brain barrier, albeit at different rates and through different mechanisms. A reduction in triglycerides is an established effect of low fat, ketogenic diets, and is thought to confer beneficial effects–. Our results indicate that MMKD could impact disease-related pathways by increasing circulating ketone bodies and increasing the ratio of circulatory free fatty acids and acylcarnitines to triglycerides, while also significantly enriching favorable PUFAs (including 22:6).

Dysregulation of ether lipid metabolism has been linked to neurodegenerative disease, metabolic disorders, and cancer. Plasmalogens, specifically, are lower in the blood and brains of those with Alzheimer’s and related to worse clinical outcomes (ADAS-Cog),,,,. Indeed, preclinical studies support interventions aimed at increasing plasmalogens, which may reduce neuroinflammation and neurodegeneration, mediated in part through enhanced AKT and ERK signaling,. We previously highlighted that the plasma level of ether lipids, notably alkyldiacylglycerols and TG(O), mediate nearly one-third of the protective effect of the APOE Ɛ2 allele in AD. Thus interventions aimed at increasing TG(O), such the MMKD, may either provide beneficial effects in patients without APOE Ɛ2 or further potentiate such effects in those with the APOE Ɛ2 allele.

We unexpectedly found an increase in several ether lipid classes after the MMKD intervention, including plasmalogens (PE(P) and PC(P)), choline and ethanolamine alkyl-ether lipids (PC(O and PE(O)), and the ether glycerolipids (TG(O)). To date, no dietary intervention has demonstrated systemic alterations to these lipid species and classes to such a degree. While both PE(O) and PE(P) increased after the MMKD, the structurally similar non-ether glycerophospholipid phosphatidylethanolamine (PE) did not change. This stark contrast was also observed within the TG/TG(O) classes, with prominent increases to TG(O) despite decreases to TG. Together, these results suggest that the MMKD may selectively impact the ether lipid classes rather than bulk changes to the lipidome as a whole.

Ether lipids are unique in their synthetic pathway and require specific enzymes found only in the peroxisome. Plasmalogens have an additional step that involves plasmanylethanolamine desaturase 1 (PEDS1) that introduces a double bond on the alkyl-linkage, which results in the vinyl-ether bond unique to this lipid class. Few approaches have been identified to increase ether lipid content in human plasma to such an extent. Alkylglycerols and similarly structured lipid metabolites can increase circulating ether lipid levels by acting as direct precursors that bypass the rate-limiting peroxisomal step and are found in modest levels in several marine oils including squid and shark liver oil.

Our results together indicate a significant upregulation of ether lipid synthesis, likely driven by increased peroxisomal number or function. It is unlikely that lipid signature of the changes with the MMKD are simply attributed to the increased dietary intake of specific food groups. Indeed, aside from increases to ether lipids as a whole, this effect is further corroborated with significant decreases to CE(24:6) with corresponding increases to CE(22:6) (Supplementary Data 2). Peroxisomal very long chain fatty acid β-oxidation is required for de novo synthesis of 22:6 from other precursors. Similarly, one existing study indicated potential improvements to peroxisomal substrate oxidative capacity in skeletal muscle with ketogenic diet and exercise. As plasmalogens and ether lipids are rate-limited in their synthesis within the peroxisome, our results indicate that MMKD impacts these metabolic pathways.

The MMKD-associated reduction in deoxyceramides may also be beneficial. Increased deoxyceramides are an established feature of metabolic disorders and have been associated with obesity in patients with type 2 diabetes mellitus. Understanding the impact of deoxyceramides in metabolic dysfunction is important given the strong relationship between systemic metabolic conditions and AD. Deoxyceramides may also contribute to multi-system age-related changes. An elegant study that compared multiple tissues (brain, fat, muscle, liver) in young versus older mice showed that deoxyceramides, as well as deoxydihydroceramides and ether-linked diacylglycerols, were increased in aging and possibly related to senescence. While we found no significant associations with ceramides when examined as a lipid class (Fig. 1a), we found species-specific relationships driven by the length of the sphingoid base. Species with a d16:1 sphingoid base were reduced, and species with more abundant d18:1 sphingoid bases were increased after the MMKD. This further supports for the need to examine species-level effects.

One of our most striking findings was that the impact of the MMKD on the plasma lipidome appears dependent on the cognitive group. While many of the lipid classes changed independently of baseline cognitive diagnosis, several lipid changes were more prominent in participants with MCI relative to those who were cognitively normal. The MCI group particularly had larger decreases to triglycerides and phosphatidylethanolamine, representing a favourable lipid profile,–. Similarly, individuals with the APOE Ɛ4 genotype were less impacted by the MMKD, which highlights the potential for the APOE genotype to influence lipid metabolism. Little is known about how cognitive status and APOE genotype impacts systemic lipid metabolism and response to dietary intervention, thus this work provides a valuable foundation for future studies. While most patients had a similar pattern of lipidome changes in response to the MMKD (Fig. 1b–d), there was marked variation in the lipidome alteration among individuals. A subset of participants displayed a substantial response to the diet, with some experiencing a nearly six-fold increase in lipid classes from baseline after the 6-week intervention. This highlights the importance of identifying those “super-responders” who may exhibit a heightened response to the diet, as it could facilitate the development of personalized therapies for those at risk of AD.

The MMKD altered the lipidome in a manner that was opposite from the lipid profiles observed in both individuals with AD cross-sectionally (Fig. 4a) and development longitudinally (Fig. 4b) from two independent studies of AD. In subsequent exploratory analyses, we found that the corresponding increases of PE(P) in circulation from the MMKD were associated with decreased ADAS-Cog12 score (Supplementary Fig. 3). This suggests that participants with a greater increase in plasmalogens, a lipid class reduced in AD,, had more benefit on a clinically meaningful endpoint.

Importantly, our results suggest that the pathologic AD lipidome signature can be attenuated through a dietary intervention. Modulating the peripheral lipidome with specific dietary intervention is far less invasive, less costly, and less prone to adverse effects than upcoming monoclonal antibody treatments, making it far more suited for early intervention considering the risk-benefit if efficacy can be demonstrated. Utilization of a dietary intervention like the MMKD as a supplementary intervention (combination therapy similar to the FINGER trial or with monoclonal antibody therapy) could provide tangible clinical benefits.

The present study features several strengths, including its prospective crossover design, advanced lipidomic methods, and well-characterized data sample. Specifically, the study design enables a more accurate evaluation of the effects of a ketogenic (and low-fat) diet on lipidomics in AD by having each participant serve as their own metabolic control. This approach effectively controls other patient characteristics, making it more likely to detect diet-related changes. Furthermore, it is likely that the benefits of a ketogenic dietary intervention extend beyond ketosis alone and supports the use of a comprehensive diet aimed at inducing ketosis rather than solely supplementing ketone bodies or medium-chain triglycerides as an attempt to achieve similar efficacy,,–.

There are several limitations that must be acknowledged. While we observed robust diet-associated lipid changes, these findings should be interpreted within the context of the sample size, which could potentially limit the generalizability of our findings across different demographics. While the randomized cross-over design enabled the identification of substantial lipid changes with MMKD intervention, we were underpowered to conclusively identify whether there were differences between sub-groups without further validation studies. It is also challenging to adequately assess the effects of APOE genotype, which plays a crucial role in lipid metabolism and AD.

We observed a profound alteration in plasma lipids following the implementation of the MMKD. However, it remains uncertain as to whether these changes are primarily driven by the metabolic effects of ketosis, by the specific constituents of the MMKD, or the combination of both. It is noteworthy that both cognitive groups were prescribed the same target diet, with the same dietician and menu, and yet the MCI group displayed a more pronounced response. Future investigations will aim to gain a deeper understanding of the underlying mechanisms. Whether the MMKD-induced modifications in the plasma lipidome are associated with beneficial brain changes will be further examined using the novel blood-based biomarkers for Alzheimer-related processes.

In conclusion, to our knowledge this study represents the first clinical investigation to examine the effects of a modified ketogenic dietary intervention on the lipidome in adults at risk for AD. Our findings demonstrate that a modified ketogenic diet led to considerable modifications in the plasma lipidome. The observed changes were generally beneficial, and more pronounced in participants with cognitive impairment. Notably, the MMKD-associated lipid changes were inverse to an established AD lipidome signature. These results suggest that a modified ketogenic diet may serve as a therapeutic intervention to reverse pathologic AD lipid changes, but more extensive mechanistic studies are required. The lower relative cost and risks associated with an MMKD enhances the appeal of this approach for use in prevention or in combination therapy for early symptomatic AD.

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